The Trypanosoma brucei sphingolipid synthase, an essential enzyme and a drug target

Abstract

Sphingolipids are important structural components of eukaryotic membranes, in addition they and their precursors are involved in signal transduction processes. In eukaryotes the biosynthetic pathway of sphingolipid biosynthesis is largely conserved. However, whilst mammals produce sphingomyelin (SM) as the major phosphosphingolipid using the enzyme SM synthase, plants and many pathogenic fungi and protozoa synthesize inositol phosphorylceramide (IPC) by IPC synthase. This enzyme is a target for anti-fungal drugs and functional orthologues have recently been identified in the insect vector-bome pathogenic kinetoplastid protozoa. These parasites are responsible for a range of neglected diseases and Trypanosoma brucei are the cause human African trypanosomiasis in many regions of Africa. The available treatments for this disease are limited, often demonstrate severe side-effects and drug resistance is increasing. T. brucei sphingolipid synthase (TbSLS), a functional orthologue of the yeast IPC synthase, may be a target for novel anti protozoals drugs. Here I show that this enzyme functions as an IPC synthase both in vitro and ex vivo. Furthermore, the TbSLS is essential for parasite growth and can be inhibited in vitro by a known anti-fungal Perhaps most importantly this drug demonstrates rapid trypanocidal activity against bloodstream form parasites. Thus TbSLS is a promising drug target